sGC is a heterodimer heme protein present in the cytoplasm, which is an enzyme that catalyzes biosynthesis of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). sGC activating substances present in the body are nitric oxide (NO) and analogous molecular species thereof (carbon monoxide and the like). cGMP is an important cellular transmitter substance in mammalian cells, which shows various biological responses via regulation by cGMP-dependent protein kinase, cGMP-dependent ion channel and cGMP-dependent phosphodiesterase and the like. For example, smooth muscle relaxation, natriuresis, suppression of platelet activation, suppression of cell proliferation, suppression of leukocyte adhesion, promotion of sugar uptake by tissues, and the like can be mentioned. Under pathologic conditions, decrease of sGC or attenuation of sGC activating ability leads to, for example, elevation of blood pressure, platelet activation, increased cell proliferation and cell adhesion, elevation of blood glucose, and decline of kidney function. As a result, hypertension, endothelial dysfunction, atherosclerosis, stable or unstable angina pectoris, thrombosis, myocardial infarction, erectile dysfunction, nephropathy, nephritis, diabetes, metabolic syndrome and the like are developed. A compound having an sGC activating action normalizes them and provides a treatment or prophylactic effect.
In hypertension, diabetes and various diseases related thereto, attenuation of blood vessel endothelial functions (for example, endothelial-dependent vasorelaxation, suppression of platelet activation, suppression of cell proliferation, suppression of inflammatory cell infiltration, suppression of phlogogenic substance production and the like) plays an important role in causing such diseases. Attenuation of endothelial function occurs due to the decreased production of nitric oxide, which is an endogenous sGC activating substance, and attenuation of sGC activation ability. Therefore, sGC activation normalizes the functions of blood vessel endothelium and blood vessel smooth muscle, recovers circulation to the peripheral tissues and metabolic function, protects tissues from organ disorders, and achieves progression and prophylaxis of pathology.
By sGC activation, cGMP is produced, and blood vessel smooth muscle is relaxed via reduction of intracellular calcium, various protein phosphorylation and the like. Thus, a compound having an sGC activating action exhibits a hypotensive action in the hypertension pathology. In addition, in ischemic cardiac diseases, it increases coronary blood flow, and shows an anti-angina pectoris action, a myocardial infarction onset-preventive and myocardial infarction prognosis-improving effects.
In diseases such as hypertension, cardiac disease, kidney disease, diabetes, metabolic syndrome and the like, insulin resistance is deeply involved in the progression of pathology and tissue disorder. Insulin causes various biological responses via NO-cGMP signal, but the insulin signal is attenuated in the above pathology. sGC activation leads to normalization of insulin signal, promoted transfer of glucose transporter to cellular membrane and the like. A compound having an sGC activating action shows a prophylactic effect on the onset and progression of the above-mentioned diseases via improvement of insulin resistance, improvement of metabolic function by promotion of sugar uptake by peripheral tissues, correction of hyperglycemia, normalization of lipid abnormality, pancreas protective action, and the like.
In diseases such as hypertension, cardiac disease, kidney disease, obesity, diabetes and the like, decreased sGC function is involved in the attenuation of diuretic action in the kidney due to the elevation of blood pressure. As a reaction to the elevation of blood pressure, NO is produced in the body due to the shear stress caused by increased kidney perfusion pressure, cGMP is produced by activation of sGC, reabsorption of sodium in the renal tubule decreases, and natriuresis is induced to lower the blood pressure. In the pathology mentioned earlier, NO-cGMP signal is attenuated. Therefore, in these pathologies, natriuresis is promoted by sGC activation, and hypotension and decrease of intrarenal glomerular pressure occur, whereby a kidney protection action is expected.
Accordingly, a compound having an sGC activating action is extremely useful for the prophylaxis or treatment of hypertension, ischemic cardiac disease, cardiac failure, kidney disease, arteriosclerotic diseases (including atherosclerosis, cerebral apoplexy, peripheral arterial obstruction and the like), atrial fibrillation, diabetes, diabetic complications and cardiovascular or metabolic disease related to metabolic syndrome and the like.
U.S. Pat. No. 6,335,334 describes a compound represented by the formula
wherein A1 is a divalent residue selected from the group consisting of phenylene, naphthylene and heteroarylene, each of which is optionally substituted;ring A2 is a benzene ring, a naphthalene ring, a saturated or partially unsaturated 3-membered to 7-membered carbon ring, a saturated or partially unsaturated or aromatic monocyclic 5-membered or 7-membered heterocycle, or a saturated or partially unsaturated or aromatic bicyclic 8-membered to 10-membered heterocycle;R1 is aryl, heterocyclyl or optionally substituted alkyl and the like;R2 is optionally substituted alkyl;R3 is hydrogen, halogen, CF3, OH, —O-alkyl and the like;N is 0, 1 or 2; andX is O or NH and the like, and a physiologically acceptable salt thereof, and describes that the compound has a soluble guanylate cyclase activation action, and is useful as an agent for the prophylaxis or treatment of cardiovascular diseases, hypertension, myocardial infarction, cardiac failure and the like. Moreover, a compound represented by the following formula
(HMR-1766) is disclosed in Example 129 (see patent document 1).
U.S. Pat. No. 7,087,644 describes a compound represented by the formula
wherein V is void, O, NR4, NR4CONR4 (R4 is alkyl, cycloalkyl and the like) and the like; Q is void, alkylene, alkenediyl, alkynediyl and the like; Y is hydrogen, NR8R9 (R8 and R9 are each independently hydrogen, alkyl, alkenyl, aryl, aromatic heterocycle, cycloalkyl and the like), aryl, aromatic or saturated heterocycle, cycloalkyl and the like; R3 is hydrogen, halogen, alkyl, halogenoalkyl and the like; m is an integer of 1-4; W is alkylene, alkenediyl and the like; U is alkyl; A is aryl, aromatic heterocycle and the like; R2 is tetrazolyl, COOR24, CONR25R26 (R24 is hydrogen, alkyl or cycloalkyl, R25 and R26 are each independently hydrogen, alkyl, cycloalkyl and the like) and the like; X is alkylene, alkenediyl and the like; n is 1 or 2; R1 is tetrazolyl, COOR30 or CONR31R32 (R30 is hydrogen, alkyl or cycloalkyl, R31 and R32 are each independently hydrogen, alkyl, cycloalkyl and the like) and the like, a stereoisomer thereof and a salt thereof, and describes that the compound has a soluble guanylate cyclase activating action and is useful as an agent for the prophylaxis or treatment of cardiovascular diseases, hypertension, thrombosis and the like. Moreover, a compound represented by the following formula
(BAY58-2667) is disclosed in Example 8 (see patent document 2).
US-A-2007/0179139 describes a compound represented by the formula
wherein Z is a phenyl ring condensed with a hetero ring, a carbon ring or heterocycle and the like; V is void, O, NR4, NR4CONR4 (R4 is alkyl, cycloalkyl and the like) and the like; Q is void, alkylene, alkenediyl, alkynediyl and the like; Y is hydrogen, NR8R9 (R8 and R9 are each independently hydrogen, alkyl, alkenyl, aryl, aromatic heterocycle, cycloalkyl and the like), aryl, aromatic or saturated heterocycle, cycloalkyl and the like; R3 is hydrogen, halogen, alkyl, haloalkyl and the like; m is an integer of 1-4; W is alkylene, alkenediyl and the like; U is alkylene; A is aryl, aromatic heterocycle and the like; R2 is tetrazolyl, COOR24, CONR25R26 (R24 is hydrogen, alkyl or cycloalkyl, R25 and R26 are each independently hydrogen, alkyl, cycloalkyl and the like) and the like; X is alkylene, alkenediyl and the like; n is 1 or 2; R1 is tetrazolyl, COOR30 or CONR31R32 (R30 is hydrogen, alkyl or cycloalkyl, R31 and R32 are each independently hydrogen, alkyl, cycloalkyl and the like) and the like, a stereoisomer thereof and a salt thereof, and describes that the compound has a soluble guanylate cyclase activating action and is useful as an agent for the prophylaxis or treatment of cardiovascular diseases, hypertension, thrombosis and the like. Moreover, a compound represented by the following formula
is disclosed in Example 1 (see patent document 3).
US-A-2008/0058314 describes a compound represented by the formula
wherein B is aryl or aromatic heterocycle; r is 0 or 1; V is void, O, NR4, NR4CONR4, NR4CO (R4 is alkyl, cycloalkyl and the like) and the like; Q is void, alkylene, alkenediyl, alkynediyl and the like; Y is hydrogen, NR6R7 (R6 and R7 are each independently hydrogen, alkyl, alkoxy, alkyloxyalkyl, cycloalkyl, aryl and the like), aryl, aromatic or saturated heterocycle, cycloalkyl and the like; R3 is hydrogen, halogen, alkyl, halogenoalkyl, alkoxy, halogenoalkoxy and the like; W is alkylene, alkenediyl and the like; U is alkylene, O, NH, S, SO or SO2; A is void, aryl, aromatic heterocycle and the like; R2 is CN, tetrazolyl, COOR26 or CONR27R28 (R26 is hydrogen, alkyl or cycloalkyl, R27 and R28 are each independently hydrogen, alkyl, cycloalkyl and the like) and the like; X is alkylene, alkenediyl and the like; R1 is CN, tetrazolyl, COOR35 or CONR36R37 (R35 is hydrogen, alkyl, cycloalkyl and the like, R36 and R37 are each independently hydrogen, alkyl, cycloalkyl and the like) and the like, stereoisomers thereof and salts thereof, and describes that the compound has a soluble guanylate cyclase activating action and is useful as an agent for the prophylaxis or treatment of cardiovascular diseases, hypertension, cardiac failure, angina pectoris and the like. Moreover, a compound represented by the following formula
is disclosed in Example 34 (see patent document 4).
WO2009/032249 describes a compound represented by the formula
wherein Z1 is CH or N; ring A is a benzene ring, a pyridine ring and the like; D1 is CH, N and the like; R7 is a hydrogen atom, a C1-6 alkyl group and the like; L1 is O, S and the like; L2 is a C2-4 alkylene group and the like; ring E is a 6- to 10-membered aryl ring and the like; R4 is a halogen atom, a C1-6 alkyl group and the like; R5 is a C1-6 alkyl group, a C2-6 alkenyl group and the like; R8 is a C1-4 alkyl group, a C2-4 alkenyl group and the like; R11 is a hydrogen atom or a C1-6 alkyl group, and a pharmaceutically acceptable salt thereof, and describes that the compound has a soluble guanylate cyclase activating action and is useful as an agent for the prophylaxis or treatment of cardiovascular diseases, hypertension, cardiac failure, angina pectoris and the like (see patent document 5).
WO2004/056815 describes a compound represented by the formula
wherein R0 is a 4- to 15-membered monocycle or fused ring (containing 1-4 hetero atoms) optionally substituted by R8 (R8 is a 6- to 14-membered aromatic hydrocarbon ring (monocyclic or fused ring) optionally substituted by a halogen atom or alkoxy, etc.) and the like; R3 and R4 are each alkyl, carboxyl and the like; R1 is C1-4 alkyl and the like; R2 is a bond, C1-4 alkyl and the like; V is a 3- to 7-membered ring; M is C1-8 alkyl etc., and describes that the compound has a FXa or VIIIa inhibitory activity (see patent document 6).
US-A-2006/122181 describes a compound represented by the formula
wherein V is N or CH; W is S or O; m is 0, 1 or 2; n is 0, or an integer of 1-4; R1 and R2 are each H or C1-4 alkyl; X is pyrazole and the like; R3 is a hydrogen atom, a halogen atom, trihalomethyl and the like; R is carboxyl and the like; L is methylene, arylene and the like; p is 0 or 1; A is alkylene; s is 0 or 1; Z is aryl etc., and describes that the compound has a protein tyrosine phosphatase 1B inhibitory activity and is useful for the treatment of diabetes, hyperlipidemia and the like (see patent document 7).
US-A-2003/104324 describes a compound represented by the formula
wherein R1 and R3 are each an aryl group optionally having substituent, a hetero ring residue and the like; R4 is a halogen atom, an alkyl group and the like; n is an integer of not less than 0 and not more than 2; k is an integer of not less than 0; L is a divalent linking group, and describes that the compound is useful as a color photographic sensitizer (see patent document 8).
US-A-2005/65196 describes a compound represented by the formula
wherein W is S or O; R is —COOR7, —X1-A1-COOR7 (R7 is H or alkyl; A1 is lower alkylene) or tetrazolyl; R1, R2, R3 and R4 are each H and the like; A is —(CH2)m—X— (m is an integer of 0 or 1-3; X is —N(R8)—, —C(R9)(R10) CO— or —CO—N(R8)— (R8 is H and the like; R9 and R10 are each H and the like); B is aryl or an aromatic heterocyclic group; R5 is H and the like; R6 is —(Y)s1-(A2)s—Z (s1 is 0 or 1; s is 0 or 1; Y is —O—, —S(O)t— (t is 0, 1 or 2), —N(R13)— (R13 is H etc.), —N(R14)—CO—, —N(R14)—SO2—, —SO2—N(R14 is H or lower alkyl) and the like, A2 is alkylene, Z is cycloalkyl, aryl, an aromatic heterocyclic group, indanyl, piperazinyl etc.), and describes that the compound has a protein tyrosine phosphatase 1B inhibitory activity and is useful for the treatment of diabetes, hyperlipidemia and the like (see patent document 9).
JP-A-4-154773 describes a compound represented by the formula
wherein R1 and R2 are each phenyl and the like; R3 is a hydroxyl group and the like; R4 is a hydrogen atom and the like; X is alkylene etc., and describes that the compound has an anti-inflammatory action (see patent document 10).
US-A-2006/205731 describes a compound represented by the formula
wherein X1, X2, X3, Z, Y1 and Y2 are each a carbon atom or a nitrogen atom; R, R1, R5 and R6 are each a hydrogen atom, an alkyl group and the like; R7 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a 5- to 6-membered saturated heterocyclic group, an aromatic heterocyclic group etc., and describes that the compound has an SyK (Spleen tyrosine kinase) inhibitory action and is useful for diseases derived from immediate allergic reaction and delayed inflammatory reaction, diseases involving antibody, diseases involving eosinophilic inflammation or platelet activation and the like (see patent document 11).
WO92/16527 describes a compound represented by the formula
wherein A is aryl and the like; B is an oxygen atom and the like; n is 0 or 1; D is —C(R)═, N and the like (R is a hydrogen atom, a halogen atom etc.); m is 0, 1 or 2; q is 0 or 1; Y is lower alkyl etc., and describes use as a bactericide agent for agriculture and horticulture (see patent document 12).